Prevalence of Selected Polymorphisms of Il7R, CD226, CAPSL, and CLEC16A Genes in Children and Adolescents with Autoimmune Thyroid Diseases.

Hashimoto's thyroiditis (HT) and Graves' disease (GD) are common autoimmune endocrine disorders in children. Studies indicate that apart from environmental factors, genetic background significantly contributes to the development of these diseases. This study aimed to assess the prevalence of selected single-nucleotide polymorphisms (SNPs) of Il7R, CD226, CAPSL, and CLEC16A genes in children with autoimmune thyroid diseases. We analyzed SNPs at the locus rs3194051, rs6897932 of IL7R, rs763361 of CD226, rs1010601 of CAPSL, and rs725613 of CLEC16A gene in 56 HT patients, 124 GD patients, and 156 healthy children. We observed significant differences in alleles IL7R (rs6897932) between HT males and the control group (C > T, p = 0.028) and between all GD patients and healthy children (C > T, p = 0.035) as well as GD females and controls (C > T, p = 0.018). Moreover, the C/T genotype was less frequent in GD patients at rs6897932 locus and in HT males at rs1010601 locus. The presence of the T allele in the IL7R (rs6897932) locus appears to have a protective effect against HT in males and GD in all children. Similarly, the presence of the T allele in the CAPSL locus (rs1010601) seems to reduce the risk of HT development in all patients.

Potential Role of Selected miRNAs in the Pathogenesis of Autoimmune Thyroid Diseases in Children and Adolescents.

BACKGROUND: Many epigenetic factors, including microRNAs, are involved in the process of changing gene expressions. Small non-coding RNA molecules, called miRNAs, are responsible for regulating gene translation by silencing or degrading target mRNAs. It is acknowledged that for many diseases, they may be novel diagnostic and prognostic biomarkers. Patients with autoimmune thyroid diseases are more likely to develop nodules in the thyroid tissue, and Hashimoto's thyroiditis and Graves' disease predispose patients to thyroid cancer. We evaluated the concentrations of microRNA molecules (miR-15a-5p, miR-126-3p, miR-142-5p, miR-21-5p, miR-150-5p) in the blood of children with thyroid disorders. In addition, we wished to identify molecules whose change in concentration predisposes to the development of thyroid cancer. AIM: The aim of this study is to evaluate selected epigenetic elements by analyzing the levels of miR-15a-5p, miR-126-3p, miR-142-5p, miR-150-5p and miR-21-5p in the blood of pediatric patients with Graves' disease (n = 25), Hashimoto's thyroiditis (n = 26) and thyroid nodular disease (n = 20) compared to a control group of healthy children (n = 17). MATERIALS AND METHODS: The study consists of groups of children and adolescents aged 10-18 years with autoimmune thyroid disease, with thyroid nodular disease compared to a control group. The miR-15a-5p, miR-126-3p, miR-142-5p, miR-21-5p and miR-150-5p molecules were determined through an immunoenzymatic assay using BioVendor reagents. RESULTS: There is a statistically significant decrease in the expression of the miR-15a-5p in children with Graves' disease (21.61 vs. 50.22 amol/µL, p = 0.03) and in patients with thyroid nodular disease compared to controls (20.23 vs. 50.22 amol/µL, p = 0.04). Higher levels of the miR-142-5p molecule are found in patients with thyroid disease (with GD-3.8 vs. 3.14 amol/µL, p = 0.01; with HT-3.7 vs. 3.14 amol/µL, p = NS, with thyroid nodular disease-4.16 vs. 3.14 amol/µL, p = 0.04). Lower levels of miR-126-3p were noted in the GD group compared to the control group (7.09 vs. 7.24 amol/µL, p = 0.02). No statistically significant changes in the expressions of miR-150-5p and miR-21-5p molecules were observed in the study groups. CONCLUSIONS: 1. The overexpression of the miR-142-5p molecule occurs in children and adolescents with thyroid diseases. 2. Decreased blood levels of miR-15a-5p predispose patients to the formation of focal lesions in the thyroid gland. 3. Identifying a lower expression of the miR-126-3p molecule in the blood of children with GD requires careful follow-up for the development of focal lesions in the thyroid gland and evaluation for their potential malignancy.

PD-1 Receptor (+) T cells are associated with the efficacy of the combined treatment with regulatory t cells and rituximab in type 1 diabetes children via regulatory t cells suppressive activity amelioration.

An imbalance between exaggerated autoaggressive T cell responses, primarily CD8 + T cells, and impaired tolerogenic mechanisms underlie the development of type 1 diabetes mellitus. Disease-modifying strategies, particularly immunotherapy focusing on FoxP3 + T regulatory cells (Treg), and B cells facilitating antigen presentation for T cells, show promise. Selective depletion of B cells may be achieved with an anti-CD20 monoclonal antibody (mAb). In a 2-year-long flow cytometry follow-up, involving 32 peripheral blood T and B cell markers across three trial arms (Treg + rituximab N = 12, Treg + placebo N = 13, control N = 11), we observed significant changes. PD-1 receptor (+) CD4 + Treg, CD4 + effector T cells (Teffs), and CD8 + T cell percentages increased in the combined regimen group by the end of follow-up. Conversely, the control group exhibited a notable reduction in PD-1 receptor (+) CD4 + Teff percentages. Considering clinical endpoints, higher PD-1 receptor (+) expression on T cells correlated with positive responses, including a higher mixed meal tolerance test AUC, and reduced daily insulin dosage. PD-1 receptor (+) T cells emerged as a potential therapy outcome biomarker. In vitro validation confirmed that successful Teff suppression was associated with elevated PD-1 receptor (+) Treg levels. These findings support PD-1 receptor (+) T cells as a reliable indicator of treatment with combined immunotherapy consisting of Tregs and anti-CD20 mAb efficacy in type 1 diabetes mellitus.

Not Only Metabolic Complications of Childhood Obesity.

The increasing incidence of obesity in the pediatric population requires attention to its serious complications. It turns out that in addition to typical, well-known metabolic complications, obesity as a systemic disease carries the risk of equally serious, although less obvious, non-metabolic complications, such as cardiovascular diseases, polycystic ovary syndrome, chronic kidney disease, asthma, thyroid dysfunction, immunologic and dermatologic conditions, and mental health problems. They can affect almost all systems of the young body and also leave their mark in adulthood. In addition, obesity also contributes to the exacerbation of existing childhood diseases. As a result, children suffering from obesity may have a reduced quality of life, both physically and mentally, and their life expectancy may be shortened. It also turns out that, in the case of obese pregnant girls, the complications of obesity may also affect their unborn children. Therefore, it is extremely important to take all necessary actions to prevent the growing epidemic of obesity in the pediatric population, as well as to treat existing complications of obesity and detect them at an early stage. In summary, physicians treating a child with a systemic disease such as obesity must adopt a holistic approach to treatment.

Mechanisms of thyrotropin receptor-mediated phenotype variability deciphered by gene mutations and M453T-knockin model.

The clinical spectrum of thyrotropin receptor-mediated (TSHR-mediated) diseases varies from loss-of-function mutations causing congenital hypothyroidism to constitutively active mutations (CAMs) leading to nonautoimmune hyperthyroidism (NAH). Variation at the TSHR locus has also been associated with altered lipid and bone metabolism and autoimmune thyroid diseases. However, the extrathyroidal roles of TSHR and the mechanisms underlying phenotypic variability among TSHR-mediated diseases remain unclear. Here we identified and characterized TSHR variants and factors involved in phenotypic variability in different patient cohorts, the FinnGen database, and a mouse model. TSHR CAMs were found in all 16 patients with NAH, with 1 CAM in an unexpected location in the extracellular leucine-rich repeat domain (p.S237N) and another in the transmembrane domain (p.I640V) in 2 families with distinct hyperthyroid phenotypes. In addition, screening of the FinnGen database revealed rare functional variants as well as distinct common noncoding TSHR SNPs significantly associated with thyroid phenotypes, but there was no other significant association between TSHR variants and more than 2,000 nonthyroid disease endpoints. Finally, our TSHR M453T-knockin model revealed that the phenotype was dependent on the mutation's signaling properties and was ameliorated by increased iodine intake. In summary, our data show that TSHR-mediated disease risk can be modified by variants at the TSHR locus both inside and outside the coding region as well as by altered TSHR-signaling and dietary iodine, supporting the need for personalized treatment strategies.

Role of miRNA in Cardiovascular Diseases in Children-Systematic Review.

The number of children suffering from cardiovascular diseases (CVDs) is rising globally. Therefore, there is an urgent need to acquire a better understanding of the genetic factors and molecular mechanisms related to the pathogenesis of CVDs in order to develop new prevention and treatment strategies for the future. MicroRNAs (miRNAs) constitute a class of small non-coding RNA fragments that range from 17 to 25 nucleotides in length and play an essential role in regulating gene expression, controlling an abundance of biological aspects of cell life, such as proliferation, differentiation, and apoptosis, thus affecting immune response, stem cell growth, ageing and haematopoiesis. In recent years, the concept of miRNAs as diagnostic markers allowing discrimination between healthy individuals and those affected by CVDs entered the purview of academic debate. In this review, we aimed to systematise available information regarding miRNAs associated with arrhythmias, cardiomyopathies, myocarditis and congenital heart diseases in children. We focused on the targeted genes and metabolic pathways influenced by those particular miRNAs, and finally, tried to determine the future of miRNAs as novel biomarkers of CVD.

Frequency and Predictive Factors of Hypoglycemia in Patients Treated With rhIGF-1: Data From the Eu-IGFD Registry.

CONTEXT: The European Increlex® Growth Forum Database (Eu-IGFD) is an ongoing surveillance registry (NCT00903110) established to collect long-term safety and effectiveness data on the use of recombinant human insulin-like growth factor-1 (rhIGF-1, mecasermin, Increlex) for the treatment of children/adolescents with severe primary insulin-like growth factor-1 deficiency (SPIGFD). OBJECTIVE: This analysis of Eu-IGFD data aimed to identify the frequency and predictive factors for hypoglycemia adverse events (AEs) in children treated with rhIGF-1. METHODS: Data were collected from December 2008 to May 2021. Logistic regression was performed to identify predictive risk factors for treatment-induced hypoglycemia AEs. Odds ratios (ORs) are presented with 95% CIs for each factor. RESULTS: In total, 306 patients were enrolled in the registry; 84.6% were diagnosed with SPIGFD. Patients who experienced ≥ 1 hypoglycemia AE (n = 80) compared with those with no hypoglycemia AEs (n = 224) had a lower mean age at treatment start (8.7 years vs 9.8 years), a more frequent diagnosis of Laron syndrome (27.5% vs 10.3%), and a history of hypoglycemia (18.8% vs 4.5%). Prior history of hypoglycemia (OR 0.25; 95% CI: [0.11; 0.61]; P = .002) and Laron syndrome diagnosis (OR 0.36; 95% CI: [0.18; 0.72]; P = .004) predicted future hypoglycemia AEs. Total hypoglycemia AEs per patient per treatment year was 0.11 and total serious hypoglycemia AEs per patient per treatment year was 0.01. CONCLUSION: Hypoglycemia occurs more frequently in patients with prior history of hypoglycemia and/or Laron syndrome compared with patients without these risk factors, and these patients should be carefully monitored for this AE throughout treatment.

Cytogenetic findings in Polish patients with suspected Fanconi anemia.

BACKGROUND: The high sensitivity of cells of Fanconi anemia (FA) patients to DNA cross-linking agents (clastogens), such as mitomycin C (MMC), was used as a screening tool in Polish children with clinical suspicion of FA. OBJECTIVES: The aim of the study was to compare chromosome fragility between 3 groups, namely non-FA, possible mosaic FA and FA patients. MATERIAL AND METHODS: The study included 100 children with hematological manifestations and/or congenital defects characteristic of FA, and 100 healthy controls. Blood samples obtained from participants were analyzed using an MMC-induced chromosomal breakage test. RESULTS: Patients with clinical suspicion of FA were divided into 3 subgroups based on the MMC test results, namely FA, possible mosaic FA and non-FA. Thirteen out of 100 patients had a true FA cellular phenotype. The mean value of MMC-induced chromosome breaks/cell for FA patients was higher than for non-FA patients (6.67 ±3.92 compared to 0.23 ±0.18). In addition, the percentage of cells with spontaneous aberrations was more than 9 times higher in FA patients than in non-FA patients. CONCLUSIONS: Our results confirmed that the MMC sensitivity test distinguishes between individuals affected by FA, those with possible somatic mosaicism, and patients with bone marrow failure for other reasons, who were classified as non-FA in the first diagnostic step. However, a definitive differential diagnosis requires follow-up mutation testing and chromosome breakage analysis of skin fibroblasts.

Determinants Related to Oxidative Stress Parameters in Pediatric Patients with Type 1 Diabetes Mellitus.

Adequate glycemic management is one of the main goals in treating type 1 diabetes mellitus (T1DM) and preventing the early onset of diabetic complications. Improperly controlled diabetes mellitus (DM) will result in oxidative stress (OS) and lead to further related health issues. Therefore, the aim of this study was to evaluate the body's ability to defend against OS depending on the duration of T1DM, metabolic management, antioxidant intake and modern glycemic monitoring systems (GMS). The study included 103 adolescents with T1DM aged 10-17 years. The control group consisted of 65 healthy peers. The patients' blood was assayed for antioxidant enzymes, minerals and toxic elements. In addition, their dietary intake of antioxidant components was assessed. The T1DM group had higher total oxidant status, oxidative stress index and Cu/Zn ratio values, higher concentrations of malondialdehyde and lower total antioxidant status (TAS) and chromium, zinc, superoxide dismutase and catalase levels than their healthy peers. The comparison between GMS types revealed favorable changes in OS parameters for the flash and continuous systems. Furthermore, an effect of vitamin A and C dietary intake on serum TAS concentrations was detected. More than 82% of the patients with high TAS fulfilled the estimated average requirement norm for vitamin A, and more than 60% fulfilled the vitamin C requirement. In youths with T1DM, it is advisable to observe the antioxidant activity of the body to prevent the accelerated development of diabetic complications.

Difficulties in Interpreting IGF-1 Levels in Short Stature Children Born Small for Gestational Age (SGA) Treated with Recombinant Human Growth Hormone (rhGH) Based on Data from Six Clinical Centers in Poland.

The assessment of IGF-1 concentrations is one of the parameters used for evaluating response to rhGH treatment. An increase in IGF-1 concentration positively correlates with growth improvement, whereas IGF-1 concentrations significantly above the reference range may increase the risk of possible side effects. The aim of this study was to evaluate the IGF-1 local reference ranges for the rhGH treatment centers concerned and to compare these values with the population reference ranges. A retrospective analysis was conducted on auxological data from 229 SGA patients who received rhGH treatment between 2016 and 2020 at six university clinical centers in Poland. The IGF-1 levels were assessed at baseline, after 12 and 24 months, and compared to the reference ranges provided by the local laboratory and to the population reference ranges. After 12 months, 56 patients (24%) presented IGF-1 values > 97th percentile for the local reference range, whereas only 8 (3.5%) did so using the population reference ranges; p < 0.001. After 24 months of treatment, the values were: 47 (33%) > 97th percentile by local vs. 6 (4.2%) by population standards; p < 0.001. Thirty-nine patients had rhGH dose reduced after 12 months, of whom twelve (25%) had IGF-1 > 97th percentile according to the local reference ranges and five (13%) > 97th percentile for the population. Our data suggest that different methods used to determine IGF-1 concentration and the different IGF-1 reference ranges result in a significant proportion of rhGH-treated children with elevated IGF-1 concentration and experiencing dose reductions, which may negatively affect growth rate.